This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Lung Cancer is a prevalent disease that takes many lives every year. Disease relapse, invasion and metastases are the main causes of death. Recent discoveries provide compelling evidence that at least some types of cancer are initiated and maintained by a small population of malignant cells called cancer-initiating stem cells (CSCs). Relapse, invasion, and metastases are explained by the fact that CSCs have a different biology than all the other tumor cells and, importantly, are resistant to chemotherapies and radiation. Lung cancer stem cells have been shown to represent about 1-15% of all tumor cells and can form tumors with injections as low as 100 cells. Evidence from published studies have demonstrated that human, as well as rodent, cancers contain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteins also express markers used to identify lung cancer stem cells, therefore, we hypothesized that ES cells and cancer stem cells share several common molecular traits. To test this hypothesis, we vaccinated mice with murine ES cells and investigated whether an anti-tumor immune response was elicited. We discovered that ES cell vaccination is very effective in preventing both implantable and carcinogen-induced lung adenocarcinoma development. Preliminary studies from our laboratory reveal that splenocytes from ES cell-immunized mice are preferentially cytotoxic to lung cancer stem cells. Experiments proposed in this application seek to expand these findings to demonstrate that ES cells immunize against lung cancer-associated CSCs and that anti-CSC immunity is responsible for preventing lung adenocarcinoma development. To fulfill the stated objectives, the following aims are proposed: 1) Demonstrate that lung cancer stem cells are targets of ES cell vaccination-induced anti-tumor immunity;and 2) Investigate the efficacy of ES cell vaccination in a transgenic model of spontaneous lung tumorigenesis. Lung cancer research has seen many significant advances in recent years, which have contributed to better therapies with improved patient outcomes. Despite that, it remains a major killer. Our proposed study will provide important insights towards developing a safe prophylactic vaccine for lung cancer onset and/or recurrence.